In recent years, as a consequence of an aging society, there has been an increase in the number of patients who need a care giver, such as patients who suffer from dementia, brain diseases, Parkinson's disease and the like. Such patients may forget to take medicine or may experience difficulty in taking medicine because of difficulty in swallowing. Thus, it is difficult for these patients to manage the medicine-taking activity by themselves. Therefore, there is a demand for other administering method than peroral administration. Besides, in the cases of patients who are treated with anti-mental illness drugs, their living is hindered due to appearance of symptoms as soon as the drug stops working. In such cases, therefore, administration should be repeated several times per day, before the drug's efficacy is lost. Frequent administration imposes a heavy burden on the patient. Accordingly, long-lasting controlled-release preparations are highly desired in all disease regions.
Most of the controlled-release preparations which have been investigated heretofore as preparations for subcutaneous administration or intramuscular administration are microspheres based on polylactic acid-glycolic acid copolymer (PLGA). For instance, there is a microcapsule preparation Leuplin (registered trademark) in which leuprorelin as a carcinostatic agent is encapsulated in a cross-linked matrix of PLGA. These microspheres based on PLGA are known to release the drug immediately upon administration (initial burst), and the concentration of the agent in the blood is immediately raised to above the effective concentration. This leads to the possibility of side effects. Besides, in the case of using PLGA, it is difficult to encapsulate a drug in a high concentration and with a high efficiency. On a clinical basis, on the other hand, there is a limit as to the dose in which the drug can be administered. Therefore, there are problems yet to be solved in relation to an improvement in the amount of drug encapsulation. Further, in the case of using PLGA, an organic solvent is used in the preparation process, so that the removal of the organic solvent from the preparation is indispensable. This is often difficult to achieve in the manufacture on an industrial scale. In addition, PLGA is said to have a serious problem in that local intensification of acid attendant on the hydrolysis can cause inflammation in the administration region.
Other than the above, some approaches have been made in which bupivacaine is encapsulated in multilayer membrane liposomes by the remote loading method. In various documents, however, the relationship between particle diameter and controlled-release properties has not been disclosed, and no finding has been obtained as to the optimum particle diameter in the controlled-release preparations. In addition, the controlled-release times disclosed in the documents cannot be said to be sufficient on a clinical basis, see (Anesthesiology 101 (2004) 133-137, International Society for Anaesthetic Pharmacology 110 (2004) 1018-1023). Furthermore, the multivesicular liposome (MVL) described in JP-T-2001-522870 has been developed as a lipid-based controlled-release drug support for local or systemic drug delivery. This approach, however, is also not yet satisfactory and still has problems to be solved, with respect to the drug encapsulation amount and the controlled-release time.